A Novel Mechanism for ART-Associated Dyslipidemia and Atherosclerosis

Grants and Contracts Details


R01HL123358 Resubmission Mechanisms of antiretroviral therapy-associated dyslipidemia and atherosclerosis (Initial title: Mechanisms of HIV PI-induced dyslipidemia and atherosclerosis) Project Summary The goal of this project is to investigate a novel mechanism linking antiretroviral (ARV) drugs with dyslipidemia and cardiovascular disease (CVD). The use of ARV drugs such as HIV protease inhibitors has been associated with dyslipidemia and increased risk of CVD but the underlying mechanisms remain elusive. We and others have identified several ARV drugs including ritonavir and amprenavir as potent agonists for the pregnane X receptor (PXR), a nuclear receptor activated by numerous drugs, xenobiotic and dietary chemicals. PXR functions as a xenobiotic sensor that induces expression of genes required for xenobiotic metabolism in the liver and intestine. PXR exhibits considerable differences in its pharmacology across species and thus its specific role in mediating the pathophysiological effects of xenobiotics in humans and animals remains obscure. We have recently revealed the pro-atherogenic effects of PXR in animal models and demonstrated that chronic PXR activation induces hyperlipidemia in wild-type mice and increases atherosclerosis in atherosclerosis-prone apolipoprotein E-deficient (ApoE-/-) mice. Our most recent study demonstrated that HIV protease inhibitor amprenavir activates PXR and induces hyperlipidemia in wild-type mice but not in PXR-deficient mice. Our central hypothesis is that chronic treatment with ARV drugs which activate PXR will lead to aberrant lipid homeostasis and accelerated atherosclerosis. We propose the following specific aims to test this hypothesis: 1) Determine the contribution of PXR towards the adverse effects of currently recommended ARV drugs on plasma lipid levels in vivo; 2) Define the molecular mechanisms through which PXR agonistic ARV drugs induce hyperlipidemia; and 3) Determine the impact of ARV drug-mediated PXR activation on atherosclerosis development in vivo. Our research will establish the role of PXR in linking ARV drugs with hyperlipidemia and CVD, and will provide novel mechanistic links explaining how anti-retroviral therapy causes atherogenic effects. These studies are broadly translational and have direct clinical consequences for patients undergoing long-term treatment with PXR agonist drugs. Keywords: HIV, ARV, dyslipidemia, atherosclerosis, HAART
Effective start/end date8/1/157/31/19


  • National Heart Lung and Blood Institute: $1,494,092.00


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